In vivo antitumour efficacy of MGI-114 (6-hydroxymethylacylfulvene, HMAF) in various human tumour xenograft models including several lung and gastric tumours

Sato, Yuji; Kashimoto, Shigeki; MacDonald, John R.; Nakano, K

doi:10.1016/s0959-8049(01)00135-6

Cited by 15 publications

(13 citation statements)

References 12 publications

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“…Growth-inhibitory measures of irofulven and illudin sensitivity were obtained from the NCI. 3 Logarithmic values of both sensitivity and AOR activity were plotted, and R 2 values were calculated using linear regression.…”

Section: Methodsmentioning

confidence: 99%

“…Sensitivity of cancers arising from nine different organs is estimated using five logarithmic concentrations of an agent and reported by concentration required to produce 50% lethality, total growth inhibition, or growth inhibition of 50%. 3 Frozen samples of each of the 58 cell lines originally used to evaluate irofulven, and illudins M and S as chemotherapeutic agents were obtained. AOR activities were measured in cytosolic fractions prepared from each of the cell lines using illudin M as substrate and analyzed by HLPC.…”

Section: Identification Of Illudin and Irofulven Metabolitesmentioning

confidence: 99%

“…Hundreds of alkylating compounds have been tested for anticancer activity; however, most are unable to provide preferential killing of cancer cells. Irofulven has proven to be an exception by performing exceptionally well in multiple human tumor xenograft experiments (3,4). Several studies have demonstrated complete cures of mice bearing tumors derived from relatively hard to kill HT29 and MV522 cell lines after irofulven administration (5,6).…”

Section: Introductionmentioning

confidence: 99%

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NADPH Alkenal/One Oxidoreductase Activity Determines Sensitivity of Cancer Cells to the Chemotherapeutic Alkylating Agent Irofulven

Dick

Xiang

Kensler

2004

Clinical Cancer Research

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Illudins S and M are extremely cytotoxic products of the fungus Omphalotus illudens. They were evaluated as possible anticancer chemotherapeutic agents but displayed unfavorable therapeutic indices. Irofulven (6-hydroxymethylacylfulvene), a less toxic, synthetic derivative of illudin S, has proven very effective in many preclinical and clinical studies. It has been postulated that metabolism via hydrogenation of the 8,9-double bonds of these molecules would unmask the electrophilic, and thus, the toxic nature of their cyclopropyl moieties. Illudins S and M were found to be rapidly metabolized by NADPH-dependent alkenal/one oxidoreductase (AOR) with maximal rates of 115.9 and 44.1 mol min ؊1 mg ؊1 , and K m s of 308 and 109 M, respectively. Irofulven was reduced at a much slower rate: V max 275 nmol min ؊1 mg ؊1 and K m 145 M. Human 293 cells transfected with an AOR overexpression vector were 100-fold more sensitive than control cells to irofulven, but displayed little differential sensitivity to illudin M. Addition of glutathione to the ␣,␤-unsaturated ketone moiety of illudin M, but not irofulven, occurred readily at physiological concentrations. Electrophilic intermediates of irofulven and illudin M that were activated by AOR were trapped with glutathione and identified by high performance liquid chromatography with tandem mass spectrometry. Samples of the 60 human tumor cell line panel used by the National Cancer Institute to evaluate potential chemotherapeutic compounds were assayed for AOR activity, which correlated positively with previously determined growth inhibitory measures for irofulven, but not illudin M or S. Collectively, these data indicate that bioactivation of irofulven by AOR plays a predominant role in its chemotherapeutic activity.

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Section: Methodsmentioning

confidence: 99%

Section: Identification Of Illudin and Irofulven Metabolitesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NADPH Alkenal/One Oxidoreductase Activity Determines Sensitivity of Cancer Cells to the Chemotherapeutic Alkylating Agent Irofulven

Dick

Xiang

Kensler

2004

Clinical Cancer Research

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“…In human tumor xenograft models, a daily times five (Dx5) schedule was associated with the highest antitumor activity among the schedules investigated (3,15). An initial Phase I trial used a 5-min i.v.…”

Section: Introductionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Irofulven Administered Weekly or Biweekly in Advanced Solid Tumor Patients

Alexandre

Raymond

Kaci³

et al. 2004

Clinical Cancer Research

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“…Irofulven (6-hydroxymethylacylfulvene, NSC#: 683863) is a semi-synthetic analog of mushroom-derived illudin toxins. Preclinical studies and clinical trials have demonstrated that it is effective against several tumor cell types [33][34][35][36][37][38][39][40][41]. It was previously demonstrated that irofulven activates ATM and its targets, NBS1, SMC1, CHK2 and p53 [42].…”

Section: Introductionmentioning

confidence: 99%

Irofulven induces replication-dependent CHK2 activation related to p53 status

Wang

Wiltshire

Senft

et al. 2007

Biochemical Pharmacology

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CHK2 and p53 are frequently mutated in human cancers. CHK2 is known to phosphorylate and stabilize p53. CHK2 has also been implicated in DNA repair and apoptosis induction. However, whether p53 affects CHK2 activation and whether CHK2 activation modulates chemosensitivity are unclear. In this study, we found that in response to the DNA damage agent, irofulven, CHK2 activation, rather than its expression, is inversely correlated to p53 status. Irofulven inhibits DNA replication and induces chromosome aberrations (breaks and radials) and p53-dependent cell cycle arrest. Pretreatment of cells with the DNA polymerase inhibitor, aphidicolin, resulted in reduction of irofulven-induced CHK2 activation and foci formation, indicating that CHK2 activation by irofulven is replication-dependent. Furthermore, by using ovarian cancer cell lines expressing dominant-negative CHK2 and CHK2-knockout HCT116 cells, we found that CHK2 activation contributes to the control of S and G2/M cell cycle arrests, but not chemosensitivity to irofulven. Overall, this study demonstrates that in response to irofulven-induced DNA damage, the activation of CHK2 is dependent on DNA replication and related to p53 status. By controlling cell cycle arrest and DNA replication, p53 affects CHK2 activation. CHK2 activation contributes to cell cycle arrest, but not chemosensitivity.

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In vivo antitumour efficacy of MGI-114 (6-hydroxymethylacylfulvene, HMAF) in various human tumour xenograft models including several lung and gastric tumours

Cited by 15 publications

References 12 publications

NADPH Alkenal/One Oxidoreductase Activity Determines Sensitivity of Cancer Cells to the Chemotherapeutic Alkylating Agent Irofulven

NADPH Alkenal/One Oxidoreductase Activity Determines Sensitivity of Cancer Cells to the Chemotherapeutic Alkylating Agent Irofulven

Phase I and Pharmacokinetic Study of Irofulven Administered Weekly or Biweekly in Advanced Solid Tumor Patients

Irofulven induces replication-dependent CHK2 activation related to p53 status

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